1. Methods for α-Sialylation Caroline Braun Townsend Group Meeting May 11, 2016

2. Sialic Acids Family of 2-keto-3-deoxy-nononic acids – Neuraminic acid: C-5 amino derivative

3. Biosynthesis of Neu5Ac Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102, 471-490.

4. Sialosides in Nature Equatorial glycosides: α-anomer Terminal sugars of glycoproteins – N- or O-linked – Linkage to galactosides: α(2  3) or α(2  6) Disialosyl structures as constituents of glycoproteins and lipids – Neu5Acα(2  8)Neu5Ac – Neu5Acα(2  9)Neu5Ac Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565. Kiefel, M. J.; von Itzstein, M. 2002, 102, 471-490.

5. Enzymatic Synthesis of O-Sialosides Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102, 471-490.

6. Synthetic Glycosidic Bond Formation Stereochemical control – Neighboring group participation (C-2) – Reaction conditions (i.e. solvent, temperature, and promoter) – Structure of donor and acceptor Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

7. Neu5Ac Donors & Stereochemical Control Issues to address: – No neighboring C-3 functionality – Prone to 2,3-elimination – Sterically hindered anomeric center Sialyl donors possess “unusual” anomeric leaving groups. Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565. Kiefel, M. J.; von Itzstein, M. 2002, 102, 471-490.

8. Sialyl Glycosylation Methods Direct – “formation of O- sialosides in one synthetic step” 2-halogeno derivatives – Cl, Br, F 2-thio derivatives – alkyl, aryl, xanthates 2-phosphites Indirect – “afford O-sialosides in 2 or more synthetic steps, one of which may be a glycosylation” Auxiliaries at C-3 – 3-O, 3-Br, 3-S, 3-Se Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

9. 2-Halogeno Derivatives 2-Chloro: synthesis of simple glycosides of Neu5Ac, or glycosylations with primary alcohols 2-Bromo: high reactivity and low stability 2-Fluoro: consistent β-selectivity Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

10. 2-Thio Derivatives Widely applied for the synthesis of sialic acid- containing oligosaccharides Good chemical stability Can be transformed into other glycosyl donors Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

11. 2-Phosphite Derivatives Widely applied for O-sialylation Require catalytic amount of activator Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

12. Evaluation of Direct Methods 2-Cl provides the best selectivity for glycosylations with simple alcohols and 1° carbohydrate alcohols Alternatives (2-SR, 2-SAr, 2-xanthate, 2-phosphites) are better for hindered carbohydrates – Better selectivity when acceptors have free diol or triol Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

13. C-3 Auxiliaries Utilizing neighboring group participation to form 2,3-trans-glycosides Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

14. Indirect Methods Drawbacks: – Additional steps – Stereoselective installation of the C-3 auxiliary Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

15. N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Oxazolidinone trans-fused ring sialyl donors – Takahashi, De Meo, and Crich De Meo, C., et al. Org. Lett. 2012, 14, 1126-1129. Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.

16. N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.

17. N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.

18. N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.

19. Probing the Nitrile Effect Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794-7797.

20. Probing the Nitrile Effect Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794-7797.

21. Probing the Nitrile Effect Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794-7797.

22. Role of Oxazolidinone Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51, 11105-11109.

23. Role of Oxazolidinone For derivatives 4 and 5 “the dipole moment of the heterocyclic system is aligned parallel to the pyranose C4-O4 and C5-N5 bonds, thereby enhancing their inherent electron-withdrawing ability.” Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51, 11105-11109.

24. Role of Oxazolidinone Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51, 11105-11109.

25. Role of Oxazolidinone Kancharla, P. K.; Kato, T.; Crich, D. J. Am. Chem. Soc. 2014, 136, 5472-5480.

26. Isothiocyanato Moiety Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54, 1275-1278.

27. Isothiocyanato Moiety Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54, 1275-1278.

28. Isothiocyanato Moiety Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54, 1275-1278.

29. 5-Ureido-Modified Sialyl Donor Kiso, M., et al. Org. Lett. 2016, 18, 1454-1457

30. α(2  8)-linked Dimers Low nucleophilicity of C-8 hydroxyl of Neu5Ac – Steric effects – Interactions with the acetamido group at C-5 – Internal hydrogen bonding Early reports utilized participating auxiliaries at C-3 Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565. Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5, 1278-1283.

31. α(2  8)-linked Dimers Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

32. α(2  8)-linked Dimers Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5, 1278-1283.

33. α(2  8)-linked Dimers De Meo, C.; Demchenko, A. V.; Boons, G-J. J. Org. Chem. 2001, 66, 5490-5497.

34. α(2  8)-linked Dimers Cleave colominic acid – Homopolymer of Neu5Acα(2  8)Neu5Ac Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

35. α(2  9)-linked Dimers High reactivity of C-9 hydroxyl group Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.

36. α(2  9)-linked Dimers Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5, 1278-1283.